In seveal mammalian species genes have been identified which control the ability of the animal to respond immunologically to specific antigens. Two broad classes of such immune response genes have been identified. One seems to be functioning at the level of antigen recognition. Many of the genes in this class are linked to the genetic loci controlling the expression of the major histocompatibility antigens of the species. Another type of immune response gene seems to be exerting its action at the level of antibody production. Some of these genes have been shown to be linked to immunoglobulin structural genes. In this project it is our objective to investigate the mechanisms through which these specific immune response genes exert their control. Toward that objective, we plan to continue our studies of guinea pig histocompatibilty - linked IR genes as a model for the genetic control of antigen recogniton, and the genetic control of in vitro anti-TNP responses of mouse spleen cells as a model for genetic control at the level of antibody production. Our studies in guinea pigs have demonstrated that antibodies directed at the linked histocompatibility antigens can suppress specific IR gene function in vitro. The suppression seems to result from an alteration of the lymphocyte membrane by the anti-histocompatibility antibody rendering the cell refractory to antigen stimulation. Our results also suggest a physical association on the lymphocyte membrane of histocompatibility antigens and the IR gene product. Our continuing research in this area will be directed at elucidating both the physical and functional relationship of histocompatibility antigens to IR gene controlled immune responses. Our studies of in vitro anti-TNP responses in mouse spleen cells have shown that it is determined by an autosomal dominant gene, and this gene seems to be expressed at the level of the B cell. Our continuing studies will be directed at both the genetic and functional aspects of this system. Using inbred recombinant strains we will map the genetic locus controlling anti-TNP responses. Using cell separation techniques we plan to better characterize the defective B cell and to identify the nature of its defect.